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IDrugs : the Investigational Drugs... Nov 1999ILEX Oncology is developing the dihydrofolate reductase inhibitor, piritrexim (discovered originally by Burroughs Wellcome), for the potential treatment of cancer. It is...
ILEX Oncology is developing the dihydrofolate reductase inhibitor, piritrexim (discovered originally by Burroughs Wellcome), for the potential treatment of cancer. It is in phase II clinical trials for malignant fibrous histiocytoma. ILEX conducted phase II clinical trials in the US and Europe with piritrexim in bladder cancer patients; however, development for this indication was discontinued in the third quarter of 1998 due to lack of efficacy. The company also initiated phase III trials in early 1997 for the treatment of AIDS-related Kaposi's sarcoma, but no further development for this indication has been reported since that time. Piritrexim was discovered by Burroughs Wellcome, which conducted phase I and II clinical trials in more than 700 patients. Due to its potentially superior properties to those of methotrexate, it was expected that piritrexim would be active in certain methotrexate-resistant tumors. Tumor responses were noted in patients with advanced bladder cancer, Kaposi's sarcoma, colon cancer, melanoma, head and neck cancer and other cancer types. In published phase II studies, piritrexim demonstrated objective response rates ranging from 23 to 75% in patients with advanced bladder cancer who failed a standard first-line chemotherapy regimen. In March 1995, ILEX acquired an exclusive, worldwide license to patents held by Burroughs Wellcome covering the composition and use of piritrexim for all cancer indications. Under the terms of the agreement, ILEX paid a licensing fee and is obligated to pay Wellcome royalties on net sales of piritrexim. In December 1996, ILEX formed a joint venture with MPI Enterprises for the manufacture and marketing of piritrexim.
PubMed: 16113990
DOI: No ID Found -
American Journal of Clinical Oncology Apr 1993We describe a patient with transitional cell carcinoma of the renal pelvis who developed respiratory dysfunction and an abnormal chest x-ray with diffuse interstitial... (Clinical Trial)
Clinical Trial
We describe a patient with transitional cell carcinoma of the renal pelvis who developed respiratory dysfunction and an abnormal chest x-ray with diffuse interstitial opacities while on chemotherapy with piritrexim, a methotrexate analog. Drug discontinuation resulted in complete resolution of the clinical and radiographic picture. The pulmonary toxicity is probably induced by piritrexim.
Topics: Aged; Antineoplastic Agents; Carcinoma, Transitional Cell; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Pulmonary Fibrosis; Pyrimidines
PubMed: 8452107
DOI: 10.1097/00000421-199304000-00013 -
British Journal of Cancer Feb 1993Piritrexim is a lipid-soluble inhibitor of dihydrofolate reductase (DHFR) that enters tumour cells rapidly by passive diffusion, cannot be polyglutamated, and is as... (Clinical Trial)
Clinical Trial
Piritrexim is a lipid-soluble inhibitor of dihydrofolate reductase (DHFR) that enters tumour cells rapidly by passive diffusion, cannot be polyglutamated, and is as effective as methotrexate in inhibiting DHFR. Bioavailability after oral dosing is approximately 75%. We performed a phase II study with oral piritrexim in non-chemotherapy pretreated patients with metastatic urothelial cancer. Thirty-three patients were treated with 25 mg three times daily for 5 consecutive days, repeated weekly, with provision for dose escalation or reduction according to the toxicity observed. Of 29 evaluable patients, one patient achieved a complete response of 19+ weeks duration, and ten patients achieved a partial response with a median duration of 22 weeks (range 16-48), for a total response rate of 38%. Piritrexim was generally well tolerated, with myelosuppression as the major toxicity, that frequently required dose modification. We conclude that piritrexim appears to be an active agent in patients with metastatic urothelial cancer when administered as a 5-day, low-dose oral schedule. It would be attractive to investigate the combination of piritrexim and cisplatin.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Cisplatin; Female; Humans; Male; Methotrexate; Middle Aged; Pyrimidines; Urologic Neoplasms
PubMed: 8431372
DOI: 10.1038/bjc.1993.71 -
American Journal of Clinical Oncology Dec 2005In this phase I study, the combination of piritrexim and gemcitabine was given to establish the maximum tolerated dose and the recommended phase II dose, and to... (Comparative Study)
Comparative Study
OBJECTIVES
In this phase I study, the combination of piritrexim and gemcitabine was given to establish the maximum tolerated dose and the recommended phase II dose, and to determine a toxicity and efficacy profile.
METHODS
Fifty-two patients with normal and impaired renal function were enrolled on this phase I study. The starting dose was piritrexim 10 mg 3 times daily (5 days of the week for 3 weeks and 1 week off each 28-day cycle) and gemcitabine 1000 mg/m2 on days 1, 8, and 15. The piritrexim was escalated in a stepwise fashion with this dose of gemcitabine and then with gemcitabine 1000 mg/m2 for days 1 and 15.
RESULTS
The recommended phase II dose of this combination was felt to be piritrexim 50 mg/day (10 mg every morning, 20 mg every noon, and 20 mg every evening) with gemcitabine 1000 mg/m2 on days 1, 8, and 15, and piritrexim 75 mg/day (25 mg thrice daily) with gemcitabine 1000 mg/m2 on days 1 and 15. Neutropenia and thrombocytopenia were the most often reported toxicity. Dose-limiting toxicity was thrombocytopenia in both groups. The number of renal-impaired patients enrolled was too small to establish a maximum tolerated dose for this group (piritrexim became unavailable), but the combination was tolerated in the patients with impaired renal dysfunction. There was 1 complete response, 1 partial response, and 1 minimal response.
CONCLUSION
The combination of piritrexim and gemcitabine was determined to be tolerable in heavily pretreated patients for use in solid tumors.
Topics: Administration, Oral; Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Deoxycytidine; Drug Synergism; Female; Folic Acid Antagonists; Gastrointestinal Diseases; Hematologic Diseases; Humans; Kidney; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Pyrimidines; Salvage Therapy; Treatment Outcome; Gemcitabine
PubMed: 16317274
DOI: 10.1097/01.coc.0000171281.13541.90 -
Antimicrobial Agents and Chemotherapy Apr 1988Piritrexim, a lipid-soluble antifolate, was evaluated for its activity against Pneumocystis carinii and Toxoplasma gondii. The concentration of piritrexim needed to...
Piritrexim, a lipid-soluble antifolate, was evaluated for its activity against Pneumocystis carinii and Toxoplasma gondii. The concentration of piritrexim needed to inhibit 50% of the catalytic activity of P. carinii dihydrofolate reductase (DHFR) was 19.3 nM, and that for T. gondii DHFR was 17.0 nM, concentrations that were 40- to over 1,000-fold less than those needed for the inhibition of activity by trimethoprim and pyrimethamine, the antifolates conventionally used in treating these organisms. Piritrexim was able to inhibit replication of T. gondii in a mouse peritoneal macrophage model at concentrations of 0.1 to 1.0 microM. Leucovorin, a reduced folate that can bypass the inhibition of DHFR by antifols in mammalian cells but not in protozoa, did not affect the ability of piritrexim to inhibit T. gondii replication. The addition of sulfadiazine, which alone was ineffective, to piritrexim allowed inhibition of T. gondii replication at lower concentrations of piritrexim than when piritrexim was used alone. These results suggest that piritrexim, alone or combined with a sulfonamide, may be a highly potent antitoxoplasma and antipneumocystis agent that could provide major pharmacologic and clinical advantages over available agents.
Topics: Animals; Folic Acid Antagonists; Mice; Mice, Inbred BALB C; Pneumocystis; Pyrimethamine; Pyrimidines; Quinazolines; Rats; Rats, Inbred Strains; Toxoplasma; Trimetrexate
PubMed: 2967669
DOI: 10.1128/AAC.32.4.430 -
Investigational New Drugs Nov 2002This was a single-agent phase II clinical trial of the antifol piritrexim in patients with advanced transitional cell carcinoma of the bladder. (Clinical Trial)
Clinical Trial
UNLABELLED
This was a single-agent phase II clinical trial of the antifol piritrexim in patients with advanced transitional cell carcinoma of the bladder.
METHODS
Patients with previously-treated, advanced urothelial carcinoma were treated with oral piritrexim at a dose of 25 mg three times daily for 5 consecutive days each week for 3 consecutive weeks followed by a 1-week rest period. Courses were repeated every 28 days.
RESULTS
Thirty-five patients were enrolled in the study, with 28 patients evaluable for survival and toxicity and 27 evaluable for response.
TOXICITY
Myelosuppression was the major dose-limiting toxicity, with WHO grade 3/4 thrombocytopenia in 4 patients, granulocytopenia in 1 patient, and anemia in 3 patients. Grade 3 nonhematologic toxicity consisted of neuropathy in 5 patients, hepatotoxicity in 2, nausea in 2, and 1 each with pulmonary toxicity and rash.
EFFICACY
Of the 27 patients evaluable for response, 2 (7%) achieved an objective response, lasting 112 and 142 days, respectively.
CONCLUSION
Piritrexim has minimal activity in patients with previously treated transitional cell carcinoma of the bladder, regardless of prior exposure to methotrexate, and further evaluation of this compound in this clinical setting is not warranted.
Topics: Aged; Aged, 80 and over; Antineoplastic Protocols; Carcinoma, Transitional Cell; Female; Humans; Male; Middle Aged; Pyrimidines; United States; Urologic Neoplasms; Urothelium
PubMed: 12448661
DOI: 10.1023/a:1020675017737 -
British Journal of Cancer Sep 1993Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase II study... (Clinical Trial)
Clinical Trial
Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase II study with piritrexim in patients with locally advanced or metastatic breast cancer. Twenty-four patients of which sixteen had received prior chemotherapy, were initially treated with 25 mg piritrexim orally administered trice daily for four days, repeated weekly, with provision for dose escalation or reduction according to observed toxicity. Of twenty-one patients evaluable for tumour response, one patient achieved a partial response which lasted for 24 weeks. Three patients had stable disease during 12 weeks of treatment, seventeen had progressive disease. Pirtrexim was generally well tolerated, in eighteen patients the dose could be escalated. Myelotoxicity was the most frequent observed toxicity of this piritrexim regimen. Leucopenia and thrombocytopenia grade 3/4 occurred in 38% of the patients sometime during treatment. Pharmacokinetic analysis of piritrexim in three patients during the first treatment cycle, revealed peak levels 1 to 2 h after an oral dose, with a trend towards a higher peak plasma levels and AUCs on the fourth dosing day compared with the first dosing day. In conclusion, orally administered piritrexim appears to be a regimen with little activity in patients with locally advanced or metastatic breast carcinoma.
Topics: Administration, Oral; Adult; Aged; Breast Neoplasms; Drug Evaluation; Female; Humans; Leukopenia; Middle Aged; Neoplasm Metastasis; Pyrimidines; Thrombocytopenia
PubMed: 8353055
DOI: 10.1038/bjc.1993.400 -
Investigational New Drugs Jul 1992
Clinical Trial
Topics: Administration, Oral; Adult; Aged; Drug Administration Schedule; Drug Evaluation; Female; Folic Acid Antagonists; Humans; Male; Middle Aged; Pyrimidines; Sarcoma; Soft Tissue Neoplasms; Treatment Outcome
PubMed: 1500271
DOI: 10.1007/BF00873124 -
The British Journal of Dermatology Nov 1993An open, 12-week, multicentre study was conducted to assess the efficacy of piritrexim isethionate in the treatment of severe psoriasis. Piritrexim isethionate is a... (Clinical Trial)
Clinical Trial Comparative Study
An open, 12-week, multicentre study was conducted to assess the efficacy of piritrexim isethionate in the treatment of severe psoriasis. Piritrexim isethionate is a lipid-soluble dihydrofolate reductase inhibitor which cannot form polyglutamates, and may be as effective as methotrexate in the treatment of psoriasis. If, as is suspected, but as yet unproven, methotrexate polyglutamates are responsible for the hepatotoxicity of methotrexate, piritrexim should be less hepatotoxic, and may offer an alternative to methotrexate therapy. Fifty-five patients were enrolled, of whom 41 completed the study. Patients were allocated to receive either 150, 225, 300, or 450 mg of piritrexim weekly, in divided doses over 72 h (low-dose groups, 150 and 225 mg), or over 36 h (300 and 450 mg groups). Twenty-four of the 41 patients who completed the study had a greater than 50% improvement in the severity of their psoriasis, as demonstrated by a reduction in the Psoriasis Severity Score, a measure analogous to the PASI scoring system. Adverse events were common, but mild, and were controlled by dose reduction. Piritrexim appears to be an effective therapy for severe psoriasis at doses of 300 and 450 mg weekly, in three divided doses over 36 h.
Topics: Drug Administration Schedule; Female; Folic Acid Antagonists; Humans; Liver; Male; Middle Aged; Psoriasis; Pyrimidines; Severity of Illness Index; Vomiting
PubMed: 8251356
DOI: 10.1111/j.1365-2133.1993.tb00489.x -
Clinical Genitourinary Cancer Mar 2008Piritrexim is reported to have a response rate of 38% in patients with chemotherapy-naive disease and 23% for second-line therapy after chemotherapy failure. We report...
BACKGROUND
Piritrexim is reported to have a response rate of 38% in patients with chemotherapy-naive disease and 23% for second-line therapy after chemotherapy failure. We report the results of a multiinstitutional, open-label, 2-stage, phase II study that further evaluates oral piritrexim in patients with urothelial carcinoma and who proved nonresponsive to standard chemotherapy.
PATIENTS AND METHODS
Eligible patients included those with bi-dimensionally measurable disease and an Eastern Cooperative Oncology Group performance status of 0-2, transitional cell carcinoma or adenocarcinoma of the urothelium, and nonresponse to > or = 1 previous standard chemotherapy regimen. Patients received piritrexim orally at 25 mg 3 times daily (every 8 hours regularly) for 5 consecutive days each week for 3 weeks, followed by a 1-week rest period. Treatment was continued until disease progression, unacceptable toxicity, or patient refusal.
RESULTS
Of the 23 patients enrolled, 19 patients and 22 patients were assessable for toxicity and response, respectively. Two patients required dose reduction because of toxicity, 2 patients discontinued study because of toxicity, and 6 patients had > or = 1 serious adverse event. Except for grade 1/2 pain and fatigue, gastrointestinal toxicities were the most commonly reported events, followed by fever, delirium, and myelosuppression. No objective responses were observed, with 2 patients demonstrating stable disease after 2-4 cycles. By the statistical design of the trial, further enrollment was halted because of lack of activity.
CONCLUSION
Regardless of modest side effects, oral piritrexim in heavily pretreated patients is inactive at this dose and schedule, confirming the results of a recent cooperative group trial.
Topics: Adenocarcinoma; Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Transitional Cell; Folic Acid Antagonists; Humans; Middle Aged; Pyrimidines; Treatment Outcome; Urologic Neoplasms
PubMed: 18501080
DOI: 10.3816/CGC.2008.n.005